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PubMed1984

[Comparative bacteriostatic activity of ticarcillin, alone and combined with clavulanic acid, 5 cephalosporins and metronidazole against 100 strains of Bacteroides fragilis].

In vitro activity against 100 strains of Bacteroides fragilis of ticarcillin alone and combined with 4 or 8 mg of clavulanic acid was compared with those of cefoxitin, cefotaxime, ceftazidime, lamoxactam , ceftriaxone and metronidazole. The Cl 90 was 29.7 mg/l for ticarcillin alone, and 1.3 and 0.5 mg/l for ticarcillin combined with 4 and 8 mg of clavulanic acid respectively. Every strain was susceptible to ticarcillin combined with clavulanic acid (CMI less than or equal to 16 mg/l) and metronidazole (CMI less than or equal to 4 mg/l). Among the cephalosporins tested, lamoxactam (Cl 90 : 1 mg/l) was the most active, followed by cefotaxime (22.7 mg/l), cefoxitin (23 mg/l), ceftriaxone (51.2 mg/l) and ceftazidime (347 mg/l).

Bacteroides fragilis↗

PubMed1989

[In vitro and in vivo activity of a combination of clavulanic acid and amoxicillin against Klebsiella pneumoniae producing extended broad-spectrum betalactamase (CTX-1, SHV-3, SHV-4)].

In vitro activity of an aminopenicillin (amoxicillin or ampicillin) combined with a betalactamase inhibitor (clavulanic acid or sulbactam, 2 mg/l) was examined against 39 strains of K. pneumoniae producing 3 types of extended broad spectrum betalactamases (CTX-1, SHV-3, SHV-4). Clavulanic acid produces the best synergistic effect. The in vivo activity of Augmentin (amoxicillin + clavulanic acid), 1 g once or twice a day, during 10 +/- 3 days was evaluated on 10 cases urinary tract infections in paraplegic patients. After 3 days, no leucocyturia was observed and bacteria were no more detected. The inhibitory effect of clavulanic acid for the extended broad-spectrum betalactamases shows that such an association could be probably chosen as well for treatment urinary infection.

Amoxicillin↗

PubMed1991

[Stability of beta-lactamase inhibitors and beta-lactam antibiotics in parenteral formulations as well as in body fluids and tissue homogenates. Comparison of sulbactam, clavulanic acid, ampicillin and amoxicillin].

Stability of beta-Lactamase Inhibitors and beta-Lactam Antibiotics in Parenteral Formulations as Well as in Body Fluids and Tissue Homogenates/Comparative studies with sulbactam, clavulanic acid, ampicillin and amoxicillin. The beta-lactamase inhibitors and the beta-lactam antibiotics are markedly different in chemical stability. The comparative examination of 4 different infusion solutions at 4 degrees C, 25 degrees C and 37 degrees C gives the following sequence of decreasing stability: sulbactam (CAS 68373-14-8), ampicillin (CAS 69-53-4), amoxicillin (CAS 61336-70-7) and clavulanic acid (CAS 58001-44-8). It is particularly striking that the two beta-lactamase inhibitors, sulbactam and clavulanic acid, behave very differently. Sulbactam is also much more stable than clavulanic acid to incubation at 37 degrees C in body fluids or in tissue homogenates. The differences in the stability of the individual drugs should be born in mind during clinical use of combination formulations such as sulbactam/ampicillin (Unacid) and clavulanic acid/amoxicillin.

Amoxicillin↗

PubMed1997

[Cholestatic hepatitis caused by amoxycillin-clavulanic acid. Report of a new case].

Toxic hepatitis is an infrequent secondary effect of amoxycillin-clavulanic acid with fewer than 30 well documented cases in the literature. Presentation is usually that of acute cholestasis several weeks after the initiation of treatment with this antibiotic. A new case of hepatic toxicity by amoxycillin-clavulanic acid is reported in a 47-years-old male who had taken this drug for a diarrhea syndrome. A brief review of the literature is made with special emphasis on the anatomopathologic aspects.

Amoxicillin↗

PubMed1988

Comparative efficacies of amoxicillin-clavulanic acid and ampicillin-sulbactam against experimental Bacteroides fragilis-Escherichia coli mixed infections.

Amoxicillin-clavulanic acid was compared with ampicillin-sulbactam in preventing the development of mixed infections produced in mice by subcutaneous inoculation of amoxicillin-resistant strains of Bacteroides fragilis and Escherichia coli. At doses designed to produce concentrations in mouse plasma similar to those obtained in humans, both amoxicillin-clavulanic acid and ampicillin-sulbactam were effective in preventing an infection caused by B. fragilis VPI 8908 mixed with E. coli E96, both strains being susceptible in vitro to each combination. However, ampicillin-sulbactam failed to arrest the progression of infections involving a more potent beta-lactamase-producing strain, E. coli 41548, even when a comparatively low inoculum was tested. In contrast, amoxicillin-clavulanic acid therapy effectively reduced the bacterial numbers at the site of infection. These data illustrate the need to treat polymicrobial infections with agents effective against the responsible aerobic as well as anaerobic bacteria.

Amoxicillin↗

PubMed1992

Effect of clavulanic acid, sulbactam and tazobactam on three different beta-lactamases from Bacteroides uniformis, Clostridium butyricum and Fusobacterium nucleatum.

The effect of three beta-lactamase inhibitors, clavulanic acid, sulbactam and tazobactam used in clinical practice were compared for their activity against purified beta-lactamases from Bacteroides uniformis, Clostridium butyricum and Fusobacterium nucleatum. The enzymes from B. uniformis and C. butyricum were produced in fermenters under controlled growth conditions and the enzyme from F. nucleatum was produced in batch cultures. Purification of the beta-lactamases was achieved by anion-exchange chromatography, gel filtration and FPLC-technique. The degree of inactivation of beta-lactamase activity was determined spectrophotometrically with nitrocefin as the substrate. The inhibitors in various concentrations were preincubated at 30 degrees C together with the enzyme for different time periods (0.5-120 min) before determination of the remaining beta-lactamase activity. The inhibitors all decreased the activity of the beta-lactamases investigated. Clavulanic acid and sulbactam were capable of reducing the enzyme activity of the B. uniformis beta-lactamase more effectively than the C. butyricum and F. nucleatum beta-lactamases. All beta-lactamases tested were more susceptible to tazobactam than to clavulanic acid and sulbactam.

Bacteroides↗

PubMed1980

Combined antibacterial activity of amoxicillin with clavulanic acid against ampicillin-resistant strains.

Strains of bacteria resistant to beta-lactam antibiotics have been increasing in number and are becoming troublesome in clinical medicine. The in vitro antibacterial activity of amoxicillin combined with clavulanic acid was determined on selected ampicillin-resistant clinical isolates. Synergistic effects were produced by amoxicillin with clavulanic acid against ampicillin-resistant strains of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, and Bacteroides fragilis. Inhibition of the beta-lactamases produced by the ampicillin-resistant strains was confirmed, especially against the penicillinases mediated by the R factor and the cephalosporinases produced by P.vulgaris and B. fragilis. The inhibitory effect of clavulanic acid against beta-lactamases was irreversible because of the high affinity of clavulanic acid to the enzymes.

Amoxicillin↗

PubMed1986

Pharmacokinetics of ticarcillin and clavulanic acid (timentin) in relation to renal function.

The disposition of coadministered ticarcillin (3 g/1.73 m2) and clavulanic acid (100 mg/1.73 m2) was examined after a 30-min infusion in 24 noninfected subjects with various degrees of renal function. Noncompartmental pharmacokinetic parameters for the individual compounds were determined from plasma concentrations and urinary excretion rates. All clearances (total, renal, and nonrenal) and urinary recoveries of unchanged drug were found to be linearly related to creatinine clearance (CLCR). The steady-state volume of distribution (9.9 and 12.9 liters for ticarcillin and clavulanic acid) approximated the extracellular fluid space and was not related to CLCR. The half-lives increased with reduced renal function and ranged from 56 to 392 min for ticarcillin and 26 to 266 min for clavulanic acid. The clearances of both drugs decreased proportionately with reduction in renal function, facilitating dosing adjustments based on CLCR. Calculations of expected steady-state maximum and minimum concentrations in plasma using constant doses and an extended dosing interval related to CLCR further rationalized use of the 30:1 drug combination ratio for all patients.

Adolescent↗

PubMed1992

Hepatitis associated with amoxycillin-clavulanic acid combination report of 15 cases.

Fifteen cases of hepatitis related to a combination of amoxycillin and clavulanic acid are reported. Most patients were aged 60 years or more and there were more men than women (sex ratio 4:1). The amoxycillin-clavulanic acid had been given at doses ranging from 0.5 to 6 g/day (mean 2 g/day) for seven to 60 days (mean 18 days). In 11 cases, the first symptoms appeared one to four weeks after stopping treatment. Jaundice was observed in all patients and was frequently associated with pruritus. Serum aminotransferase activities were increased in all patients and were generally two to 10 times the upper limit of normal. Serum alkaline phosphatase activity was considerably increased, from two to seven times the upper limit of normal. Histological examination of the liver, performed in seven patients, showed centri- or panlobular cholestasis in all cases, associated with granulomatous hepatitis in one. The prognosis of amoxycillin-clavulanic acid induced hepatitis seemed to be good. None of the patients exhibited biological or clinical features of hepatic failure and the course of the disease was characterised by the resolution of jaundice within one to eight weeks and a complete recovery within four to 16 weeks. Taking into account the number of treated subjects and reported cases, we estimated the risk of developing hepatitis with this drug combination to be very low, probably below 1/100,000. Our data suggest that the risk of hepatotoxicity may be increased in elderly men given lengthy treatment. The association of hepatitis and signs of hypersensitivity may suggest an immunoallergic mechanism of hepatotoxicity in some patients.

Adult↗

PubMed1985

Safety and effectiveness of ticarcillin plus clavulanic acid in the treatment of community-acquired acute pyelonephritis in adult women.

An open study was conducted to evaluate the safety and effectiveness of ticarcillin plus clavulanic acid in the treatment of 18 adult women with community-acquired Escherichia coli acute pyelonephritis. Eleven of the 18 patients had a history of urinary tract infections, primarily acute pyelonephritis. Six patients had blood culture results positive for E. coli in addition to positive urine culture results. Ticarcillin plus clavulanic acid was administered as the 3.2 g formulation to 11 patients and as the 3.1 g formulation to the other seven. The mean duration of treatment was 9.2 days. Five of the 18 (28 percent) patients had clinical and bacteriologic cures; there were 11 (69 percent) relapses or reinfections and two (11 percent) clinical failures. Adverse reactions (all reversible) were reported in 11 (61 percent) patients, the most frequent of which was phlebitis. These results should prompt further investigation into the treatment of acute pyelonephritis with ticarcillin plus clavulanic acid versus other antibiotics.

Acute Disease↗

PubMed1984

[Effect of the amoxicillin-gentamicin combination in the presence of clavulanic acid on 8 strains of amoxicillin-resistant bacteria].

The in vitro inhibitory activity of a combination of amoxicillin and gentamicin was assayed by the microdilution technique in liquid medium on 8 amoxicillin-resistant strains, with the addition of clavulanic acid at a concentration of 4 micrograms/ml. A synergistic effect was demonstrated when clavulanic acid was added. The FIC index was particularly low for the 2 Staphylococcus aureus strains tested (0.19 and 0.25), and slightly higher for the 2 Escherichia coli (0.25 and 0.5) and 2 Proteus vulgaris (0.5 and 0.5) strains. Synergism was less apparent for the 2 Klebsiella pneumoniae strains tested (0.63 and 0.75). Without clavulanic acid, a synergistic effect was found on only three strains: one Staphylococcus aureus, one Klebsiella and one Proteus. However, the high levels of MICs at which these effects were observed preclude the clinical usefulness of the association. We conclude that the synergistic effect of the amoxicillin-gentamicin combination on susceptible strains is confirmed on amoxicillin-resistant strains when clavulanic acid is added.

Amoxicillin↗

PubMed1994

[Properties of a cephalosporinase produced by Proteus penneri inhibited by clavulanic acid].

P. penneri produces an inducible cephalosporinase, as many Enterobacteriaceae. Nevertheless this betalactamase is susceptible to clavulanic acid which is an exception also encountered for P. vulgaris. The authors studied the enzyme produced by P. penneri 14HBC resistant to cefotaxime (MIC 16 mg/l) isolated in Spain in 1992. This betalactamase of isoelectric point 6.65 hydrolyzes first generation cephalosporins, amoxycillin and poorly ticarcillin as it occurs for all cephalosporinases. However, this enzyme hydrolyzes strongly oxyimino-cephalosporins: cefuroxime, cefotaxime, cefepime, cefpirome as it occurs with extended-spectrum betalactamases. Cephamycins and imipenem are not substrates. Clavulanic acid has a very good affinity for this betalactamase which is inactivated progressively. These properties are similar to those of the enzyme of P. vulgaris Ro104 of isoelectric point 8.3 which, contrarily to other cephalosporinases, belongs to the structural Ambler's class A.

Anti-Bacterial Agents↗

PubMed1987

Activity of cefazolin and two beta-lactamase inhibitors, clavulanic acid and sulbactam, against Bacteroides fragilis.

One hundred clinical isolates of the Bacteroides fragilis group of bacteria were tested by agar dilution for susceptibility to cefazolin alone or in combination with clavulanic acid or sulbactam. For cefazolin, the MIC for 50% of the isolates (MIC50) was 32 micrograms/ml, the breakpoint for susceptibility. With the addition of 0.5 micrograms of clavulanic acid per ml, the MIC for 90% of the isolates (MIC90) was 8 micrograms/ml, well within the achievable range of concentrations in serum or tissue. Similarly, with the addition of 0.5 micrograms of sulbactam per ml, the MIC90 was 16 micrograms/ml. The addition of a higher concentration (4.0 micrograms/ml) of clavulanic acid or sulbactam resulted in MIC90S which were fourfold lower than those with 0.5 micrograms/ml. A fixed ratio of cefazolin-beta-lactamase inhibitor of 4:1 resulted in an MIC50 and MIC90 which were intermediate between the 0.5- and 4.0-micrograms/ml fixed concentration of beta-lactamase inhibitor.

Bacteroides fragilis↗

PubMed1977

Clavulanic acid: a beta-lactamase-inhiting beta-lactam from Streptomyces clavuligerus.

A novel beta-lactamase inhibitor has been isolated from Streptomyces clavuligerus ATCC 27064 and given the name clavulanic acid. Conditions for the cultivation of the organism and detection and isolation of clavulanic acid are described. This compound resembles the nucleus of a penicillin but differs in having no acylamino side chain, having oxygen instead of sulfur, and containing a beta-hydroxyethylidine substituent in the oxazolidine ring. Clavulanic acid is a potent inhibitor of many beta-lactamases, including those found in Escherichia coli (plasmid mediated), Klebsiella aerogenes, Proteus mirabilis, and Staphylococcus aureus, the inhibition being of a progressive type. The cephalosporinase type of beta-lactamase found in Pseudomonas aeruginosa and Enterobacter cloacae P99 and the chromosomally mediated beta-lactamase of E. coli are less well inhibited. The minimum inhibitory concentrations of ampicillin and cephaloridine against beta-lactamase-producing, penicillin-resistant strains of S. aureus, K. aerogenes, P. mirabilis, and E. coli have been shown to be considerably reduced by the addition of low concentrations of clavulanic acid.

Amidohydrolases↗

PubMed1988

Rate of bactericidal activity for Branhamella catarrhalis of fleroxacin compared with that of amoxycillin-clavulanic acid.

The rate of bactericidal activity of fleroxacin was compared with that of the combination of amoxycillin and clavulanic acid (in the proportion of 4 to 1) on beta-lactamase producing strains of Branhamella catarrhalis. The rate of bactericidal activity of 1 mg/l was as rapid as that of 1 mg/l of amoxycillin-clavulanic acid combination. This rate was not significantly more rapid if the concentrations of fleroxacin were increased to 10 mg/l. In conclusion, the bactericidal activity of fleroxacin is at least as good as that of the combination of amoxycillin and clavulanic acid. Fleroxacin showed a bactericidal effect for B. catarrhalis at concentrations that would be achieved in humans.

Amoxicillin↗

PubMed1982

Pharmacokinetics of amoxicillin and clavulanic acid administered alone and in combination.

The pharmacokinetics of amoxicillin and clavulanic acid, administered alone and in combination, were studied in six male and six female normal human volunteers. Each ingested 500 mg of amoxicillin or 125 mg of clavulanic acid or the above agents in combination in randomized sequences. The results indicate that most of the parameters tested for either substance are essentially independent of the presence of the other one.

Adult↗

PubMed2002

Resistance to beta-lactamase inhibitor protein does not parallel resistance to clavulanic acid in TEM beta-lactamase mutants.

In order to compare patterns of resistance to inhibition by clavulanic acid with patterns of resistance to inhibition by a beta-lactamase inhibitor protein (BLIP), R164S, R244S, and R164S/R244S mutant forms of TEM beta-lactamase were prepared by site-directed mutagenesis. When kinetic parameters were determined for these mutant and wild-type forms of TEM, the single mutants showed properties that were similar to those in the literature but the double mutant showed properties that were very different. The R164S/R244S double mutant form of TEM retained its resistance to inhibition by clavulanic acid (characteristic of the R244S mutation) but lost all its ability to hydrolyze ceftazidime (characteristic of the R164S mutation). While these characteristics are contrary to those previously reported for an R164S/R244S double mutant, this discrepancy resulted from the use of a defective mutant in the earlier study. Both the single and double mutant forms of TEM remained highly sensitive when tested for inhibition by BLIP, showing only slightly increased resistance compared to that of the wild type; this pattern of resistance is quite different from the pattern of clavulanic acid resistance. The slight increases in resistance to inhibition by BLIP seen in the mutants may have been related to the fact that all of the mutations effected changes in the net charge on the TEM protein that could impede interactions with BLIP.

Ampicillin Resistance↗

PubMed1983

In vitro susceptibility of Mycobacterium fortuitum to amoxicillin or cephalothin in combination with clavulanic acid.

The comparative in vitro activity of cefoxitin, cephalothin, amoxicillin, and clavulanic acid in combination with the latter two agents against 13 isolates of Mycobacterium fortuitum was evaluated by agar dilution susceptibility testing. Amoxicillin was more active than cephalothin but less active than cefoxitin against the strains tested. Clavulanic acid in combination with these beta-lactams usually improved the activity by one or two dilutions compared with the beta-lactams alone.

Amoxicillin↗